“Cardiovascular disease or disorder” is intended to mean any cardiovascular disease or disorder known in the art, including congestive heart failure, complications associated with diabetes mellitus, hyperhomocysteinemia, hypercholesterolemia, atherosclerosis, inflammatory heart disease, valvular heart disease, restenosis, hypertension (e.g. pulmonary hypertension, labile hypertension, idiopathic hypertension, low-renin hypertension, salt-sensitive hypertension, low-renin, salt-sensitive hypertension, thromboembolic pulmonary hypertension; pregnancy-induced hypertension; renovascular hypertension; hypertension-dependent end-stage renal disease, hypertension associated with cardiovascular surgical procedures, hypertension with left ventricular hypertrophy, and the like), diastolic dysfunction, coronary artery disease, myocardial infarctions, cerebral infarctions, arteriosclerosis, atherogenesis, cerebrovascular disease, angina (including chronic, stable, unstable and variant (Prinzmetal) angina pectoris), aneurysm, ischemic heart disease, cerebral ischemia, myocardial ischemia, thrombosis, platelet aggregation, platelet adhesion, smooth muscle cell proliferation, vascular or non-vascular complications associated with the use of medical devices, vascular or non-vascular wall damage, peripheral vascular disease, neointimal hyperplasia following percutaneous transluminal coronary angiograph, vascular grafting, coronary artery bypass surgery, thromboembolic events, post-angioplasty restenosis, coronary plaque inflammation, embolism, stroke, shock, arrhythmia, atrial fibrillation or atrial flutter, thrombotic occlusion and reclusion cerebrovascular incidents, and the like.
Many individuals are at an elevated risk of suffering serious to life-threatening cardiovascular events, including infarction (heart attack), cardiac arrest, congestive heart failure, stroke, peripheral vascular disease and/or claudication. The risk factors are numerous and widespread throughout the world population. They include cigarette smoking, diabetes, hypercholesterolemia (high serum cholesterol), hypertension, angina, systemic lupus erythematosus, prior heart attacks or strokes, hemodialysis, hyperhomocysteine levels, obesity, sedentary lifestyle, receiving an organ transplant, atherosclerosis, and others. There is a need for a safe and convenient pharmaceutical formulation that would effectively reduce the risk of incurring a cardiovascular event in individuals who have these risk factors.
The treatments and drugs discovered or known in the art for cardiovascular disease includes but are not limited to beta-blockers, for example, atenolol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, timolol; Alpha blockers, for example, doxazosin, phentolamine, indoramin, phenoxybenzamine, prazosin, terazosin, tolazoline; mixed alpha and beta blockers, for example, bucindolol, carvedilol and labetalol.
Beta-blocker, for example, metoprolol acts by blocking the adrenergic stimulation of the heart and thus reduces the oxygen demand of the cardiac tissue. Apparently, this explains their beneficial effects in angina pectoris and cardioprotective action in myocardial infarction. In addition, beta-blockers normalize blood pressure in a large proportion of patients with arterial hypertension, which probably is due to an additional action on the control of peripheral resistance to blood-flow.
Metoprolol (Formula I) is a beta1-selective (cardioselective) adrenoreceptor-blocking agent. It is commercially available in two salt forms; one of them is tartrate salt available as Lopressor® tablets and the other is succinate salt available as Toprol®-XL tablets. The Toprol®-XL tablets contain 23.75 mg, 47.5 mg, 95 mg and 190 mg of metoprolol succinate equivalent to 25 mg, 50 mg, 100 mg and 200 mg of metoprolol tartrate, USP, respectively. Metoprolol is indicated in the treatment of hypertension, heart failure and angina pectoris.
Initial therapy with a diuretic or beta-blocker has been the usual first approach for treating cardiovascular disorders. ACE inhibitors, calcium channel blockers and angiotensin receptors blockers are also effective as first-line therapy. The physician is therefore required to choose from above classes of agents for initial therapy.
Calcium channel blockers play important role in contractile processes of cardiac muscle and vascular smooth muscle by regulating the movement of extracellular calcium ions into these cells through specific ion channels. Calcium channel blockers work by blocking voltage-gated calcium channels (VGCCs) in cardiac muscle and blood vessels. This decreases intracellular calcium leading to a reduction in muscle contraction. In the heart, a decrease in calcium available for each beat results in a decrease in cardiac contractility. In blood vessels, a decrease in calcium results in less contraction of the vascular smooth muscle and therefore an increase in arterial diameter (CCBs do not work on venous smooth muscle) a phenomenon called vasodilation.
Angiotensin II receptor blockers (ARBs), also known as angiotensin II receptor antagonists, ATI-receptor antagonists or “sartans”, are a group of drugs which modulate the renin-angiotensin-aldosterone system. Their main uses are in the treatment of hypertension (high blood pressure), diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure. Angiotensin II receptor blockers, block the activation of angiotensin II AT1 receptors. Blockade of AT1 receptors directly causes vasodilation, reduces secretion of vasopressin, and reduces production and secretion of aldosterone, amongst other actions. The combined effect reduces blood pressure.
ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension (high blood pressure) and congestive heart failure, although they may also be prescribed for cardiac failure, diabetic nephropathy, renal disease, systemic sclerosis, left ventricular hypertrophy and other disorders. Originally synthesized from compounds found in pit viper venom, they inhibit angiotensin-converting enzyme (ACE), a component of the blood pressure-regulating renin-angiotensin system.
Angiotensin-converting enzyme inhibitors (ACE inhibitors) reduce the activity of the renin-angiotensin-aldosterone system. One mechanism for maintaining the blood pressure is the release of a protein called renin from cells in the kidney (to be specific, the juxtaglomerular apparatus). This produces another protein, angiotensin, which signals the adrenal gland to produce aldosterone. This system is activated in response to a fall in blood pressure (hypotension), as well as markers of problems with the salt-water balance of the body, such as decreased sodium concentration in the distal tubule of the kidney, decreased blood volume and stimulation of the kidney by the sympathetic nervous system. In such situations, the kidneys release renin, which acts as an enzyme and cuts off all but the first 10 amino acid residues of angiotensinogen (a protein made in the liver, and which circulates in the blood). These 10 residues are then known as angiotensin I. Angiotensin I is then converted to angiotensin II by angiotensin converting enzyme (ACE).
Angiotensin converting enzyme inhibitors (ACE inhibitors) block the conversion of angiotensin I to angiotensin II. They, therefore, lower arteriolar resistance and increase venous capacity; increase cardiac output, cardiac index, stroke work, and volume; lower renovascular resistance; and lead to increased natriuresis (excretion of sodium in the urine).
Based on the disease condition and diagnosis, the physicians tend to prescribe a combination of two or more anti-hypertensive drugs to a patient. Such combinations are expected to provide a better control over various cardiovascular diseases. The said combinations can be given as two separate drugs administered separately at same time or at different timings. Several fixed dose combinations of anti-hypertensive drugs are available in the market. Wherever possible, a fixed dose combination is used by physicians to simplify the dosing regimen. Some of the commercially available cardiovascular drug combinations include Lopressor HCT® (Metoprolol and Hydrochlorthiazide); Valturna® (Aliskiren hemifumarate and Valsartan); Exforge HCT® (Amlodipine besylate, Hydrochlorothiazide); Exforge® (Amlodipine besylate and Valsartan); Diovan HCT® (Hydrochlorothiazide and Valsartan); Twynsta® (Amlodipine besylate and Telmisartan); Micardis HCT® (Hydrochlorothiazide and Telmisartan); Hyzaar® (Hydrochlorothiazide and Losartan potassium); Avalide® (Hydrochlorothiazide and Irbesartan); Atacand HCT® (Candesartan cilexetil and Hydrochlorothiazide); Tribenzor® (Amlodipine besylate, Hydrochlorothiazide and Olmesartan medoxomil); Azor® (Amlodipine besylate and olmesartan medoxomil); Benicar HCT® (Hydrochlorothiazide and Olmesartan medoxomil); Vaseretic® (Enalapril maleate and Hydrochlorothiazide); Quinaretic® (Hydrochlorothiazide and Quinapril hydrochloride); Accuretic® (Hydrochlorothiazide and Quinapril hydrochloride); Zestoretic® (Hydrochlorothiazide and Lisinopril); Prinzide® (Hydrochlorothiazide and Lisinopril); Lotrel® (Amlodipine besylate and Benazepril hydrochloride); Lotensin HCT® (Benazepril hydrochloride and Hydrochlorothiazide); Capozide® (Captopril and Hydrochlorothiazide); and Tarka® (Trandolapril and Verapamil hydrochloride). However, these fixed dose combinations does not provide physician an option to modulate the dose of drugs within these fixed dose combinations according to need of a patient.
These cardiovascular combinations are also prescribed along with other drugs such as cardioprotectant, platelet aggregation inhibitors, anticoagulants, antipsychotics, etc. This multiple medication administration, complex drug regimen, and frequent dose administration complicates the patient's compliance. Since cardiovascular disorders are often chronic disorders, complex drug regimen involving several drugs has a negative impact on patient's life leading to non-compliance. Most of the patient's tend to forget dosage regimen quite often. Further, it becomes difficult for the physician to prescribe appropriate doses of different drugs when used in combination. Moreover, because of the complexity of dosage regimen, it becomes difficult for the pharmacist to explain the treatment regimen to the patient being treated. Thus, non-compliance occurs at all three levels i.e. at physician, pharmacist and patient's level. In order to improve compliance there is a need of an appropriate compliance package, which is self explanatory to patient comprising appropriate fixed dose combinations.
U.S. Pat. No. 4,572,909 discloses amlodipine; U.S. Pat. No. 4,446,325 discloses aranidipine; U.S. Pat. No. 4,772,596 discloses azelnidipine; U.S. Pat. No. 4,220,649 discloses barnidipine; U.S. Pat. No. 4,448,964 discloses benidipine; U.S. Pat. No. 5,856,346 discloses clevidipine; U.S. Pat. No. 4,466,972 discloses isradipine; U.S. Pat. No. 4,885,284 discloses efonidipine; and U.S. Pat. No. 4,264,611 discloses felodipine.
U.S. Pat. No. 5,399,578 discloses Valsartan; European Patent No. 0 502 314 discloses Telmisartan; U.S. Pat. No. 5,138,069 discloses Losartan; U.S. Pat. No. 5,270,317 discloses Irbesartan; U.S. Pat. Nos. 5,583,141 and 5,736,555 discloses Azilsartan; U.S. Pat. No. 5,196,444 discloses Candesartan; U.S. Pat. No. 5,616,599 discloses Olmesartan; and U.S. Pat. No. 5,185,351 discloses Eprosartan.
U.S. Pat. No. 4,374,829 discloses enalapril; U.S. Pat. No. 4,587,258 discloses ramipril; U.S. Pat. No. 4,344,949 discloses quinapril; U.S. Pat. No. 4,508,729 discloses perindopril; U.S. Pat. No. 4,374,829 discloses lisinopril; U.S. Pat. No. 4,410,520 discloses benazepril; U.S. Pat. No. 4,508,727 discloses imidapril; U.S. Pat. No. 4,316,906 discloses zofenopril; U.S. Pat. Nos. 4,046,889 and 4,105,776 discloses captopril; and U.S. Pat. No. 4,337,201 discloses fosinopril.
Pharmaceutical compositions comprising beta-adrenergic blockers and/or calcium channel blockers are disclosed in following patent and non-patent literature.
Chinese Patent Application No. 101249083 discloses a twice-a-day sustained-release matrix preparation containing amlodipine and metoprolol, wherein 25 to 45 percent of the drug is released in a first hour, 45 to 75 percent in a fourth hour, and more than 75 percent in an eighth hour.
PCT Patent Application No. 1999018957 discloses a pharmaceutical combination of atenolol with amlodipine besylate.
U.S. Pat. No. 4,942,040 discloses a pharmaceutical preparation giving a controlled and extended release of both a dihydropyridine, e.g. felodipine and a 3-adrenoreceptor antagonist, namely metoprolol.
Kumaravelrajan et al., (Lipids in Health and Disease (2011), 10-51) discloses a controlled porosity osmotic pump tablet (CPOP) system to deliver Nifedipine (NP) and Metoprolol (MP) in a controlled manner up to 12 hours. The developed osmotic system was effective in the multi-drug therapy of hypertension.
Trenkwalder et al., (Journal of human hypertension, (1995), 9 (2), S37-42) discloses an extended-release (ER) formulation, combining felodipine, 5 mg, and metoprolol, 50 mg.
CTRI/2008/091/000190 discloses a randomised, open-label; parallel group, multicentric study comparing the efficacy and safety of fixed-dose-combinations of Metoprolol XL plus Amlodipine with individual components of the combination.
CTRI/2009/091/000269 discloses a single arm trial assessing the efficacy and tolerability of a fixed-dose combination of metoprolol and amlodipine in essential hypertension.
Pharmaceutical compositions comprising beta-adrenergic blockers and/or angiotensin II receptor blockers are disclosed in following patent and non-patent literature.
PCT Patent Application No. 201128016 discloses a formulation comprising an immediate-release compartment including beta-adrenergic blockers nebivolol and an extended-release compartment including angiotensin II receptor blockers losartan.
Indian Patent Application No. 2205/MUM/2007 discloses a pharmaceutical combination comprising β1 receptor antagonist nebivolol and angiotensin II receptor blocker telmisartan.
Indian Patent Application No. 1324/MUM/2008 discloses a pharmaceutical composition of angiotensin II receptor blocker such as losartan potassium and a beta-selective adrenoreceptor blocking agent metoprolol succinate in monolithic matrix technology.
CTRI/2010/091/001438 discloses a single arm trial to evaluate the safety and efficacy of fixed dose combination of olmesartan and metoprolol succinate ER in hypertensive patients with cardiovascular disease.
Pharmaceutical compositions comprising beta-adrenergic blockers and/or ACE inhibitors are disclosed in following patent and non-patent literature.
PCT Patent Application No. 2007010501 ('501) discloses a once a day pharmaceutical composition comprising a beta-blocker and ACE inhibitor, wherein the beta blocker is present in an extended release form and the ACE inhibitor is present in an immediate release form. The composition may exhibit release of metoprolol over a period of 12-13 hours.
U.S Patent Application No. 20050032879 ('879) discloses use of a beta-blocker and an ACE-inhibitor in combination for the treatment of hypertension. The release of drugs from the dosage form may be provided over a period of 12-15 hours and therefore the combination may not provide adequate synergistic effects.
Metoprolol has been classified as a class I substance according to the Biopharmaceutics Classification Scheme (BCS), meaning that it is highly soluble and highly permeable. The drug is readily and completely absorbed throughout the whole intestinal tract but is subject to extensive first pass metabolism resulting in incomplete bioavailability (about 50%). Amlodipine besylate, a representative example in class of calcium channel blockers is slightly soluble in water and sparingly soluble in ethanol. Amlodipine also undergoes extensive first pass metabolism. Thus, formulating a once-a-day dosage form of highly water soluble metoprolol in a fixed dose combination comprising an extended release metoprolol and highly water soluble actives belonging to calcium channel blockers, angiotensin II receptor blockers and ACE inhibitors is a challenging task for a pharmacist.
None of the above mentioned prior arts provides a once-a-day fixed dose formulation comprising an extended release metoprolol with a calcium channel blocker, angiotensin II receptor blocker or ACE inhibitor, which is safe and has an enhanced therapeutic effect over the existing individual drug therapy. The prior arts disclosing pharmaceutical composition comprising metoprolol in combination with one or more calcium channel blocker, angiotensin II receptor blocker or ACE inhibitor does not provide a once-a-day dosage form with desired synergistic therapeutic effect. The combination disclosed in the prior arts also does not address the uniform release and bioavailability related aspects of either of metoprolol, calcium channel blocker, calcium channel blocker, angiotensin II receptor blocker or ACE inhibitor when formulated into a once-a-day dosage form. Present inventors developed a matrix dosage form comprising combination of β1 blocker drugs in combination with calcium channel blocker, angiotensin II receptor blocker or ACE inhibitor. The release profile obtained from matrix tablets was erratic and varied from batch to batch. It was found that due to highly soluble and highly permeable nature of metoprolol, it is difficult to formulate and achieve an extended release once a day formulation in matrix dosage form. Further, preparing a fixed dose combination comprising an extended release metoprolol was also a major challenge as it was difficult to achieve the desired therapeutic release of the combination when combined into a single unit dosage form. Therefore, there is an ongoing need for the development of new dosage forms comprising an extended release metoprolol with calcium channel blocker, angiotensin II receptor blocker or ACE inhibitor which are safe and effective.